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The Distribution and Survival Association of Genetic Polymorphisms in Thai Patients with Hepatocellular Carcinoma According to Underlying Liver Disease.
Background/objectivesThe influence of single-nucleotide polymorphisms (SNPs) on hepatocellular carcinoma (HCC) in terms of etiological factors remains to be explored. This study evaluated the distribution of PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs6834314 and overall survival of HCC patients with metabolic dysfunction-associated steatotic liver disease (MASLD-HCC) and viral-related HCC (VIRAL-HCC).MethodsThis study included 564 patients with HCC: 254 with MASLD-HCC and 310 with VIRAL-HCC. The SNPs were determined by real-time PCR using TaqMan assays.ResultsThe mean ages of patients with MASLD-HCC and VIRAL-HCC were 68.4 vs. 60.9 years (p < 0.001), with a significant difference between groups. The prevalence of PNPLA3 GG genotype in MASLD-HCC was significantly higher in MASLD-HCC than in VIRAL-HCC (24.0% vs. 15.5%, OR = 1.86, 95% CI = 1.14-3.05, p = 0.009). Similarly, the prevalence of TM6SF2 TT genotype in MASLD-HCC and VIRAL-HCC was 7.1% vs. 2.6% (OR = 3.39, 95% CI = 1.36-9.21, p = 0.003), while HSD17B13 GG genotype in the corresponding groups was 7.1% vs. 12.6% (OR = 0.53, 95% CI = 0.27-1.01, p = 0.039). The overall median survival of MASLD-HCC was significantly shorter than that of the VIRAL-HCC group (42 vs. 66 months, p = 0.035). In Cox regression hazard analysis, HSD17B13 GG genotype was significantly associated with a lower mortality rate in MASLD-HCC (HR = 0.38, 95% CI = 0.18-0.81, p = 0.011). In contrast, PNPLA3 and TM6SF2 were not associated with overall survival in patients with MASLD-HCC or VIRAL-HCC.ConclusionsOur data demonstrated that the prevalence of the SNPs significantly differed between MASLD-HCC and VIRAL-HCC. The HSD176B13 GG genotype was also associated with a survival benefit in Thai patients with MASLD-HCC. Thus, assessing the HSD176B13 genotype might be beneficial in risk stratification and potential therapeutic inhibition of HSD17B13 among patients with MASLD-HCC.
Screening for visceral leishmaniasis in humans and animals in Laos.
BackgroundVisceral leishmaniasis (VL) is a vector-borne protozoan disease with a global distribution, with higher rates of infection associated with HIV. Zoonotic species of Leishmania have also been reported infecting domestic animals. Reports of VL are increasing in Southeast Asia, with over 200 cases reported in Thailand since the first autochthonous case in 1999, and recently the first patients have been reported from Vietnam and Cambodia. However, no cases of VL have been reported from Lao PDR (Laos) and clinical awareness of the disease is limited. This study aimed to investigate whether Leishmania is circulating in Laos by screening people living with HIV, stored samples from unselected patients with fever, and ruminants taken to abattoirs.MethodsPeople living with HIV from two specialist units in Vientiane Capital had EDTA blood taken and DNA extracted and tested for Leishmania by nested-PCR. Stored serum samples from patients presenting to Mahosot Hospital with fever and without known HIV infection, as well as serum from goats, cows and buffalo taken to abattoirs in four provinces in Laos were tested for Leishmania using the InBios Kalazar Detect Rapid Test.ResultsThere were 1015 people living with HIV tested between 2021 and 2024 for Leishmania by nested-PCR, all of whom were negative. Of 511 human serum samples collected between 2005 and 2023, two (0.4%) tested positive by rapid test. These samples were identified as coming from the same patient, with samples taken 10 months apart. There were 5/159 (3.1%) ruminant serum samples positive by rapid test with 3/45 (6.7%) buffalo positive, 2/47 (4.3%) goat positive and 0/67 cows positive.ConclusionsThis study suggests Leishmania may be circulating in Laos with undetected cases. Further investigation is needed to confirm the findings, determine at-risk populations and increase clinical awareness of the disease. This study expands on the current regional knowledge on leishmaniasis and shows the need for further epidemiological studies.
Quantifying the effects of antibiotic resistance and within-host competition on strain fitness in Streptococcus pneumoniae.
Competition plays a key role in shaping the structure and diversity of bacterial populations. In many clinically important bacterial species, strains compete at multiple scales: at the between-host scale for new hosts to colonise, and at the within-host scale during co-colonisation. Characterising these multiple facets of competition plays an important role in understanding bacterial ecology. This is particularly relevant for antibiotic resistance, where competition between antibiotic-susceptible and resistant strains determines resistance dynamics. In this work, we perform survival analyses on a large longitudinal dataset of Streptococcus pneumoniae carriage to quantify how within-host competition affects the rates of clearance and establishment of pneumococcal strains. We find that the presence of a within-host competitor is associated with a 33% increase in clearance and a 54% reduction in establishment. Priority effects and serotype differences partially predict the outcomes of this within-host competition. Further, we quantify the effects of antibiotic resistance on between- and within-host components of fitness. Antibiotic consumption is associated with increased clearance rate for both susceptible and resistant strains, albeit to a higher extent in susceptible strains. In the absence of antibiotics, we find some evidence that resistance is associated with increased susceptibility to within-host competition, suggesting a fitness cost of resistance. Overall, our work provides quantitative insights into pneumococcal competition across scales and the role of this competition in shaping pneumococcal epidemiology.
COVID-19 Surveillance in Madagascar and Urban Burkina Faso: Addressing Underreporting of Disease Burden Through Integrative Analysis of Diverse Data Streams
Abstract Background Coronavirus disease 2019 (COVID-19) caused substantial disease and death worldwide since December 2019, but the burden was lower in Africa than in high-income countries. To address potential underreporting, we modeled severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and disease burden in Burkina Faso and Madagascar. Methods Prospectively enrolled patients who presented with fever at sentinel healthcare facilities were assessed for active SARS-CoV-2 infection. Household members of SARS-CoV-2–infected patients were prospectively followed for confirmed SARS-CoV-2 infection. Archived serum specimens that spanned the pandemic onset in Madagascar to the start of prospective surveillance were tested for anti–SARS-CoV-2 immunoglobulins. Data from these multiple sources contributed to an integrated analysis to calibrate an epidemiologic mass action model. Results COVID-19 accounted for a substantial fraction of healthcare-ascertained febrile illness in both Burkina Faso and Madagascar, with symptom profiles consistent with those previously reported. SARS-CoV-2 vaccination coverage was very low in Burkina Faso and unavailable in Madagascar. The household secondary attack rate was 28% (95% confidence intervals [CI], 22%–35%] in Madagascar and 31% (95% CI: 9%–68%) in Burkina Faso, indicating substantial transmission of the disease within households in both locations. Model simulations estimated that the actual number of SARS-CoV-2 infections was at least nine times higher than the reported number of febrile COVID-19 cases. Conclusions Africa has faced persistent challenges due to underinvestment in vaccination programs and disease surveillance programs. There was substantial underreporting of COVID-19 cases during the pandemic in both countries. Our findings call for improving systems and resources in disease surveillance during epidemic and interepidemic periods in these countries.
Comparative analysis of fully automated vs. conventional ventilation in postoperative cardiac surgery patients: Impact on alarms, interventions, and nurse acceptance.
ObjectivesTo compare the number of alarms, interventions and nurses' acceptance of automated ventilation with INTELLiVENT-ASV versus conventional ventilation strategy in patients receiving postoperative ventilation after cardiac surgery.MethodsThis preplanned secondary analysis of the 'POSITiVE' randomized clinical trial compared INTELLiVENT-ASV (automated ventilation) with conventional ventilation in postoperative cardiac surgery patients. The number of critical alarms and manual ventilator interventions were compared during the first three hours of ventilation or until extubation. Nurses' acceptance was assessed using a Technology Acceptance Model 2-based questionnaire and a user acceptance score from 1 to 10.ResultsPOSITiVE randomized 220 patients (109 to automated and 111 to conventional ventilation). The average number of critical alarms per monitoring hour was similar between the automated and conventional group (5.6 vs 5.7; p = 0.823). The automated group required fewer manual interventions per monitoring hour for both ventilation control (0.7 vs 1.9; p ConclusionsAutomated ventilation for postoperative cardiac surgery patients had similar alarm frequencies as conventional ventilation, but reduced the number of interventions and showed higher nurses' acceptance, indicating its potential to optimize patient care and reduce nurses' workload.Implications for clinical practiceOur findings suggest that automated ventilation modes like INTELLiVENT-ASV can reduce the frequency of manual interventions and improve nurses' acceptance, which may help alleviate nurses' workload for postoperative cardiac surgery patients.
Targeted, Condensed Lung Ultrasound Training Program for Image Interpretation: A Prospective Multicenter Observational Study in Intensive Care Unit Professionals.
IntroductionStandardized training in lung ultrasound is lacking. Given time constraints and challenges in accessing training, there is a need for condensed, focused training programs. This study aims to assess the effect of a targeted, condensed two hour training session on the competency of intensive care unit (ICU) healthcare professionals in interpreting lung ultrasound clips.MethodsThis is a multicenter prospective study in ICU healthcare professionals from six centers. Subjects received a two hour lung ultrasound training: a lecture on principles and recognition of (patho)physiological patterns followed by hands-on training. Subjects competency was tested using twenty pre-recorded lung ultrasound clips before and after training. Retainment of knowledge was tested after six to twelve months in a subset of subjects. Subjects were deemed competent if they reached a test score ≥80%.ResultsSixty-six subjects (49% intensivist, 44% with no lung ultrasound experience) were included. 61 subjects (92%) reached the predetermined competency level after training. After the training, the highest percentage of subjects (n = 27, 97%) who reached the competency threshold were those with no prior experience in lung ultrasound. Post-test scores were significantly higher than pre-test scores (87%, 95% CI (86, 89) vs 76%, 95% CI (73, 79), p < 0.001) with a median improvement of 9, 95% CI (7, 11) percentage points. After six to twelve months all retested subjects (n = 12) maintained competency.ConclusionA short two hour training program may be sufficient for ICU healthcare professionals to achieve competency in lung ultrasound interpretation, even for subjects with no prior lung ultrasound experience. Further studies are needed to validate these findings in different settings and assess competency in bedside ultrasound acquisition.
Recent advances in immunopathogenesis and clinical practice: mastering the challenge-managing of non-tuberculous mycobacteria.
Non-tuberculous mycobacteria (NTM) are widespread environmental pathogens that can lead to significant disease burden, particularly in immunocompromised individuals, but also in those with a normal immune system. The global incidence of NTM is increasing rapidly, with Mycobacterium avium complex (MAC) being one of the most common types. The immunopathogenesis of the MAC involves a complex interaction between the bacteria and the host immune system. MAC survives and replicates within macrophages by preventing the fusion of phagosomes and lysosomes. The mycobacteria can neutralize reactive oxygen and nitrogen species produced by the macrophages through their own enzymes. Additionally, MAC modulates cytokine production, allowing it to suppress or regulate the immune response. Diagnosing MAC infections can be challenging, and the effectiveness of available treatments may be limited due to MAC's unpredictable resistance to various antimycobacterial drugs in different regions. Treating MAC infection requires a collaborative approach involving different healthcare professionals and ensuring patient compliance. This review aims to shed light on the complexities of MAC infection treatment, discussing the challenges of MAC infection diagnosis, pharmacological considerations, such as drug regimens, drug monitoring, drug interactions, and the crucial role of a multidisciplinary healthcare team in achieving the best possible treatment outcomes for patients.
Effect of spontaneous breathing on ventilator-free days in critically ill patients-an analysis of patients in a large observational cohort.
BackgroundMechanical ventilation can injure lung tissue and respiratory muscles. The aim of the present study is to assess the effect of the amount of spontaneous breathing during mechanical ventilation on patient outcomes.MethodsThis is an analysis of the database of the 'Medical Information Mart for Intensive Care (MIMIC)'-III, considering intensive care units (ICUs) of the Beth Israel Deaconess Medical Center (BIDMC), Boston, MA. Adult patients who received invasive ventilation for at least 48 hours were included. Patients were categorized according to the amount of spontaneous breathing, i.e., ≥50% ('high spontaneous breathing') and <50% ('low spontaneous breathing') of time during first 48 hours of ventilation. The primary outcome was the number of ventilator-free days.ResultsIn total, the analysis included 3,380 patients; 70.2% were classified as 'high spontaneous breathing', and 29.8% as 'low spontaneous breathing'. Patients in the 'high spontaneous breathing' group were older, had more comorbidities, and lower severity scores. In adjusted analysis, the amount of spontaneous breathing was not associated with the number of ventilator-free days [20.0 (0.0-24.2) vs. 19.0 (0.0-23.7) in high vs. low; absolute difference, 0.54 (95% CI, -0.10 to 1.19); P=0.101]. However, 'high spontaneous breathing' was associated with shorter duration of ventilation in survivors [6.5 (3.6 to 12.2) vs. 7.6 (4.1 to 13.9); absolute difference, -0.91 (95% CI, -1.80 to -0.02); P=0.046].ConclusionsIn patients surviving and receiving ventilation for at least 48 hours, the amount of spontaneous breathing during this period was not associated with an increased number of ventilator-free days.
Practice of adjunctive treatments in critically ill COVID-19 patients-rational for the multicenter observational PRoAcT-COVID study in The Netherlands.
BackgroundPatients with coronavirus disease 2019 (COVID-19) may need hospitalization for supplemental oxygen, and some need intensive care unit (ICU) admission for escalation of care. Practice of adjunctive and supportive treatments remain uncertain and may vary widely between countries, within countries between hospitals, and possibly even within ICUs. We aim to investigate practice of adjunctive and supportive treatments, and their associations with outcome, in critically ill COVID-19 patients.MethodsThe 'PRactice of Adjunctive Treatments in Intensive Care Unit Patients with Coronavirus Disease 2019' (PRoAcT-COVID) study is a national, observational study to be undertaken in a large set of ICUs in The Netherlands. The PRoAcT-COVID includes consecutive ICU patients, admitted because of COVID-19 to one of the participating ICUs during a 3-month period. Daily follow-up lasts 28 days. The primary endpoint is a combination of adjunctive treatments, including types of oxygen support, ventilation, rescue therapies for hypoxemia refractory to supplementary oxygen or during invasive ventilation, other adjunctive and supportive treatments, and experimental therapies. We will also collect tracheostomy rate, duration of invasive ventilation and ventilator-free days and alive at day 28 (VFD-28), ICU and hospital length of stay, and the mortality rates in the ICU, hospital and at day 90.DiscussionThe PRoAcT-COVID study is an observational study combining high density treatment data with relevant clinical outcomes. Information on treatment practices, and their associations with outcomes in COVID-19 patients in highly and urgently needed. The results of the PRoAcT-COVID study will be rapidly available, and circulated through online presentations, such as webinars and electronic conferences, and publications in peer-reviewed journals-findings will also be presented at a dedicated website. At request, and after agreement of the PRoAcT-COVID steering committee, source data will be made available through local, regional and national anonymized datasets.Trial registrationThe PRoAcT-COVID study is registered at clinicaltrials.gov (study identifier NCT04719182).
Mechanical Ventilation and the Titer of Antibodies as Risk Factors for the Development of Transfusion-Related Lung Injury
Purpose. Onset of transfusion-related acute lung injury (TRALI) is suggested to be a threshold-event. Data is lacking on the relation between titer of antibodies infused and onset of TRALI. We determined whether onset of TRALI is dependent on the titer of MHC-I antibodies infused in a combined model of ventilator-induced lung injury and antibody-induced TRALl.Methods. BALB/c mice were ventilated for five hours with low (7.5 ml/kg) or high (15 ml/kg) tidal volume. After three hours of MV, TRALI was induced by infusion of 0.5 mg/kg, 2.0 mg/kg or 4.5 mg/kg MHC-I antibodies. Control animals received vehicle. After five hours of MV, animals were sacrificed.Results. MV with high tidal volumes resulted in increased levels of all markers of lung injury compared to animals ventilated with low tidal MV. In ventilator-induced lung injury, infusion of 4.5 mg/kg of antibodies further increased pulmonary wet-to-dry ratio, pulmonary neutrophil influx and pulmonary KC levels, whereas infusion of lower dose of antibodies did not augment lung injury. In contrast, mice ventilated with low tidal volumes did not develop lung injury, irrespective of the dose of antibody used.Conclusions. In the presence of injurious MV, onset of TRALI depends on the titer of antibodies infused.
Case Report: Genetic evolution of Burkholderia pseudomallei during treatment leading to antibiotic resistance and disease relapse.
Background Melioidosis is a significant yet neglected cause of sepsis in tropical regions, particularly in southeast Asia, with poor clinical outcomes. It is a growing threat with an expanding global footprint. The causative organism, Burkholderia pseudomallei, is intrinsically resistant to most first-line empiric antibiotic regimens, but acquired resistance to recommended antibiotics for this infection is uncommon. Nonetheless, the genetic determinants of resistance in this species remain poorly elucidated. Case presentation A 60-year-old farmer presented in septic shock to a hospital in Laos, and B. pseudomallei was grown from blood cultures. Following initial antibiotic treatment with meropenem and co-trimoxazole, his infection relapsed. Several subsequent B. pseudomallei isolates from the patient were resistant to multiple antibiotics, and whole genome sequencing demonstrated that this phenotype was associated with a novel 54-kb genomic deletion. This deletion, on chromosome 1, includes the 5’ end of amrR – which encodes a regulator of an efflux pump known to be important in conferring meropenem resistance – as well as 46 other genes, some of which have not been characterised. Treatment was targeted to the new antibiogram, requiring a further prolonged intravenous course and second-line oral eradication therapy. The patient made a full recovery. Conclusions Mutations in Burkholderia pseudomallei lead to increased virulence and drug resistance. Repeat microbiological sampling of patients who do not make clinical improvement as anticipated is essential, with repeat full antimicrobial susceptibility testing on subsequent isolates. Characterisation of drug-resistant mutants is required to understand mechanisms of resistance and to predict phenotypes from whole genome sequencing.
Microhaplotype deep sequencing assays to capture Plasmodium vivax infection lineages.
Plasmodium vivax elimination is challenged by dormant liver stages (hypnozoites) that can reactivate months after initial infection resulting in relapses. Relapsing infections confound antimalarial clinical efficacy trials due to the inability to distinguish between recurrences arising from blood-stage treatment failure (recrudescence), reinfection or relapse. Genetic relatedness of paired parasite isolates, measured by identity-by-descent (IBD), can provide important information on whether individuals have had single or multiple mosquito inoculations, thus informing on recurrence origin. We developed a high-throughput amplicon sequencing assay comprising 93 multi-SNP (microhaplotype) markers to determine IBD between P. vivax clinical isolates. The assay was evaluated in 745 global infections, including 128 infection pairs from a randomized controlled trial (RCT) (ClinicalTrials.gov NCT01680406). Simulations demonstrate low error in pairwise IBD estimation at the panel (RMSE
Climate-driven marmot-plague dynamics in Mongolia and China.
The incidence of plague has rebounded in the Americas, Asia, and Africa alongside rapid globalization and climate change. Previous studies have shown local climate to have significant nonlinear effects on plague dynamics among rodent communities. We analyzed an 18-year database of plague, spanning 1998 to 2015, in the foci of Mongolia and China to trace the associations between marmot plague and climate factors. Our results suggested a density-dependent effect of precipitation and a geographic location-dependent effect of temperature on marmot plague. That is, a significantly positive relationship was evident between risk of plague and precipitation only when the marmot density exceeded a certain threshold. The geographical heterogeneity of the temperature effect and the contrasting slopes of influence for the Qinghai-Tibet Plateau (QTP) and other regions in the study (nQTP) were primarily related to diversity of climate and landscape types.
Infection and risk factors of human and avian influenza in pigs in south China.
The coinfection of swine influenza (SI) strains and avian/human-source influenza strains in piggeries can contribute to the evolution of new influenza viruses with pandemic potential. This study analyzed surveillance data on SI in south China and explored the spatial predictor variables associated with different influenza infection scenarios in counties within the study area. Blood samples were collected from 7670 pigs from 534 pig farms from 2015 to 2017 and tested for evidence of infection with influenza strains from swine, human and avian sources. The herd prevalences for EA H1N1, H1N1pdm09, classic H1N1, HS-like H3N2, seasonal human H1N1 and avian influenza H9N2 were 88.5, 64.5, 60.3, 57.8, 12.9 and 10.3 %, respectively. Anthropogenic factors including detection frequency, chicken density, duck density, pig density and human population density were found to be better predictor variables for three influenza infection scenarios (infection with human strains, infection with avian strains, and coinfection with H9N2 avian strain and at least one swine strain) than were meteorological and geographical factors. Predictive risk maps generated for the four provinces in south China highlighted that the areas with a higher risk of the three infection scenarios were predominantly clustered in the delta area of the Pearl River in Guangdong province and counties surrounding Poyang Lake in Jiangxi province. Identification of higher risk areas can inform targeted surveillance for influenza in humans and pigs, helping public health authorities in designing risk-based SI control strategies to address the pandemic influenza threat in south China.
Impact and mitigation of near infrared absorption in quantitative Transmission Raman Spectroscopy.
Transmission Raman Spectroscopy is an analytical technique commonly used for uniformity content analysis of manufactured pharmaceutical products to quantify the active pharmaceutical ingredients and excipients in the final formulation. Such samples are subjected to a variety of physical-chemical stressors during the manufacture such as compaction force or thickness variations. These effects can impact the effective optical paths Raman photons traverse inside the sample and hence impose different attenuation to emerging Raman photons through near infrared absorption resulting in distortions of Raman spectral profiles. These distortions can propagate to quantitative models and manifest themselves as systematic errors in predictions. In this work, we studied the impact of thickness, porosity and compaction force variations on the predictive capability of a quantitative model and propose a basic spectral standardization technique to correct for it. We observed an improvement in the statistical metrics used to evaluate the performance of the model built on the whole calibration set (RMSE from 2.5 % to 2.0 %) and near complete elimination of the present bias between the most extreme values of compaction (from 8.40 to ∼0 %) accompanied by the corresponding reduction in residuals (RMSE from 8.63 % to 2.06 %).